Computer‐Aided Design of Opioid Receptors Dual Action Ligands with Mitigated Side Effects as a Potential New Avenue for Analgesic and Substance Abuse Treatment

Abstract

Opioid Receptors have long been targeted for analgesic and substance abuse treatment. However, current drugs targeting opioid receptors, e.g., morphine, have side effects such as tolerance, dependence and respiratory depression that put the public health at high risk. Thus, there is an unmet need for the discovery of new opioid receptor ligands that have improved profiles than the current marketed drugs. We previously identified that dual action ligands of mu opioid receptor agonist/delta opioid receptor antagonist could exert analgesic activity with mitigated side effects, and thus may have an advantage over the current drugs. Subsequently, we have explored the structure-activity relationship of a 5′-aryl-14-alkoxypyridomorphinan scaffold that exhibits such a dual action profile. In addition to evaluating the pharmacokinetic properties of this scaffold, we also have performed computational docking studies of mu, delta, and kappa opioid receptors in their agonist and antagonist bound states. Docking results and structural analysis have unveiled key residues that may explain the agonist/antagonist mechanism as well as variant residues among different opioid receptor isoforms that can be targeted for selectivity. Encouragingly, the results from in vivo animal studies showed analgesic activity and less side effects versus morphine, such as tolerance, rewarding effect, and respiratory depression. These results suggest that this chemical series possessing the pyridomorphinan scaffold is worthy for further exploration for either novel analgesic agents or substance abuse treatment.